Carbon nanotubes exhibit exceptional structural properties and conductivity, and are being incorporated into diverse manufacturing processes, yet little is known about the risks that these novel molecules pose to human health. Emerging observations indicate that pulmonary exposure to carbon nanotubes induce a fibrotic response in the lungs that is related at least in part due to their size and shape. Preliminary experiments from our group indicate that pulmonary exposure to multiwalled carbon nanotubes (MWCNT) alters hemostasis, vascular reactivity, and myocardial injury resulting from acute coronary occulusion and reperfusion. Furthermore, comparison to other nano-scale particles, including elemental carbon (Printex 90), ceramic nanoparticles and ambient particulate matter, indicates that cardiotoxicity of nano-scale particles is related more to the particle composition and surface characteristics than to its shape. In this project, we propose to test the hypothesis that respirable MWCNT are cardiotoxic, and how MWCNTtissue interaction impacts their biological activity. MWCNT of uniform length (10 to 20 |am) and well-defined surface characteristics will be generated through a collaboration with the Institute of Regenerative Medicine at Winston-Salem Health Sciences Center and NanoTechLabs, Inc. Investigators at the East Carolina University will deliver the nanotubes by acute inhalation to mice, verify the pulmonary distribution and define the acute and chronic effects of particle exposure on hemostasis, vascular reactivity, and myocardial response to ischemia. The modifications to be compared represent alteration to the pristine MWCNT and surface functionalization paradigms that are common in nanotechnology and will include a) nitrogen-doping, b) surface carboxylation, and c) surface amination. The effects of these modifications will be tested in each of the following Specific Aims: Specific Aim 1. Evaluate the fate of inhaled MWCNT, Specific Aim 2. Demonstrate that aspiration of multiwalled carbon nanotubes alters hemostasis and myocardial response to ischemia and reperfusion. Specific Aim 3. Test the hypothesis that inhalation of MWCNT alters vascular reactivity via impared adenosine signaling. Specific Aim 4. Assess the role of endothiela nitric oxide, oxidative stress and vascular function in MWCNT cardiotoxicity.